This invention relates to skin care compositions which may contain retinoids and other ingredients which generally improve the quality of the skin, particularly human facial skin. More particularly, the present invention relates to chemically stable skin care compositions comprising an oil-in-water emulsion and certain retinoids and to methods for making such compositions. This invention also relates to packaging and methods of packaging such compositions so as to preserve their chemical stability.
Skin care compositions containing retinoids have become the focus of great interest in recent years. Retinoic acid, also known as Vitamin A acid or tretinoin, is well-known for the treatment of such skin conditions as acne and products containing retinoic acid are commercially available in various forms from the Dermatological Division of Ortho Pharmaceutical Corporation. Such products, for example, include Retin A* creams, an oil-in-water emulsion of retinoic acid containing as an oil-soluble antioxidant, butylated hydroxytoluene (BHT); Retin A* liquid, a solution of retinoic acid in a polyethylene glycol/ethanol solvent employing BHT as an antioxidant; and Retin A* gel, which comprises retinoic acid in a gel vehicle comprising ethyl alcohol as the solvent, hydroxypropyl cellulose as the thickener or gelling agent and BHT as an antioxidant. These retinoic acid containing products have proven stable and capable of providing active ingredients after extended periods of storage.
More recently, however, wider use of retinoids has been suggested for treatments other than acne such as, for example, the treatment of skin against photoaging and sun damage. Many individuals who have had a good deal of sun exposure in childhood will show the following gross cutaneous alterations in later adult life: wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) and various premalignant growths (often subclinical). These changes are most prominent in light-skinned persons who burn easily and tan poorly. These cumulative effects of sunlight are often referred to as xe2x80x9cphotoagingxe2x80x9d. Although the anatomical degradation of the skin is most advanced in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness and loss of elasticity are very late changes.
The problem of skin aging is addressed in U.S. Pat. No. 4,603,146, wherein Vitamin A acid in an emollient vehicle is suggested as a treatment. Further, in U.S. Pat. No. 4,877,805, it is suggested that a number of retinoids are useful for restoring and reversing sun damage of human skin.
When considering the use of retinoids in skin care products, it is believed that certain retinoids such as, for example, retinol (Vitamin A alcohol), retinal (Vitamin A aldehyde) and retinyl esters such as retinyl acetate and retinyl palmitate would be preferred over retinoic acid. This is because they are endogenous compounds naturally occurring in the human body and essential for good growth, differentiation of the epithelial tissues and reproduction. Additionally, excess retinol is stored in the human body largely in an inactive ester form, e.g., retinyl palmitate and, to some extent, retinyl acetate. The aldehyde, retinal, also a preferred form, is an active metabolite of retinol. Accordingly, attention has turned toward formulating skin care compositions which contain these preferred, naturally occurring retinoids.
In formulating products containing such retinoids, the same properties sought with respect to the retinoic acid formulas are desirable for other retinoid containing compositions. Specifically, much attention is directed toward providing a composition which is aesthetically pleasing and which can deliver active ingredients after a substantial shelf life. Not surprising, in formulating products containing such retinoids, the art is led to the experience gained in the already existing formulas containing retinoic acid. Typically, such formulas comprise oil-in-water emulsions wherein the retinoic acid is carried within the oil phase and is protected from oxidation by employing an oil-soluble antioxidant. With respect to the form of the emulsion, oil-in-water emulsions have been preferred in that, as compared to water-in-oil emulsions for example, they are non-occlusive, non-greasy, compatible with other such emulsion products, easy to remove from the skin and are regarded as more aesthetically pleasing as well as being more economical to manufacture. With respect to chemical stability of the active ingredient, it has been experienced that the retinoic acid in the oil phase is, in the main, well protected by including in such oil phase an oil soluble antioxidant.
Thus, various oil-in-water emulsions containing retinoic acid and BHT, as oil-soluble antioxidant have been described and sold, for example, in U.S. Pat. No. 3,906,108, U.S. Pat. No. 4,66,805, and U.S. Pat. No. 4,247,547. The retinoic acid containing compositions described in these patents have proven to be, or are said to be, chemically stable. Therefore, a number of skin care products have appeared in the marketplace incorporating other retinoids, including, for example, retinol, retinal and retinyl esters such as retinyl acetate and retinyl palmitate, and these unsurprisingly emulate the formulas of the commercial retinoic acid compositions, i.e., are oil-in-water emulsions protected by oil-soluble antioxidants. Unfortunately, it has been found that these other retinoids in such compositions quickly lose their activity and either oxidize or isomerize to non-efficacious chemical forms with the result that the amount of retinoid actually available to provide the beneficial effects of the product is reduced, in an unacceptably short period of time, to an ineffective quantity and eventually to only trace quantities.
There have been attempts to formulate a stable composition comprising retinol, retinal, retinyl acetate and retinyl palmitate in oil-in-water emulsions, such as in U.S. Pat. No. 4,826,828. Avon Products, Inc., the assignee of U.S. Pat. No. 4,826,828, sells two skin care products called Bioadvance and Bioadvance 2000. Each of these products is supplied in two bottles, portions of which are mixed together just prior to use. U.S. Pat. No. 4,720,353 (Bell) describes water-in-oil emulsion carriers for various medicaments and drugs intended for topical application to the skin. Other water-in-oil type emulsions have been described in EP 0 343 444 A2 (Siemer et al.) and EP 0 330 496 A2 (Batt).
Clum et al., in U.S. patent application Ser. No. 07/719,264, now abandoned, describe stable water-in-oil compositions containing a retinoid and a stabilizing system selected from the group consisting of: (a) a chelating agent and at least one oil-soluble antioxidant; (b) a chelating agent and at least one water-soluble antioxidant; and (c) an antioxidant present in each of the oil and water phases of the emulsion. This composition retains at least about 60% of the retinoids after 13 weeks of storage at 40xc2x0 C. Although this system is quite stable and useful in retinoid-containing products, it is nevertheless a water-in-oil emulsion and retains all the attributes, advantages and disadvantages of such a formulation. It is therefore an object of this invention to provide an oil-in-water formulation which is stable and acceptable for use on the skin.
In accordance with the present invention, it has now been unexpectedly found that certain retinoids may be successfully stabilized against chemical degradation by incorporating them into oil-in-water emulsions comprising a specifically defined stabilizing system. In addition, this invention relates to oil-in-water emulsion compositions which are cosmetically elegant.
The retinoids which can be stabilized against chemical degradation in accordance with the principles of the present invention are retinol (Vitamin A alcohol), retinal (Vitamin A aldehyde), retinyl acetate, retinyl palmitate and mixtures thereof. It is also theorized that other retinoids, including synthetic retinoids and retinoid-like chemicals may benefit from inclusion in the formulations of this invention.
As used herein, the xe2x80x9cchemical stabilityxe2x80x9d or xe2x80x9cstabilityxe2x80x9d of a retinoid is defined in terms of the percentage of the specified retinoid which is retained in its original chemical form after the composition has been stored for a specified period of time at a specified temperature. Thus, if the original concentration of all-trans retinol in an absolute ethanol solution were 0.20% by weight and, after two (2) weeks"" storage at room temperature (21xc2x0 C.xc2x11xc2x0 C.), the concentration of all-trans retinol were 0.18% by weight, then the original solution would be characterized as having a chemical stability of 90% after two weeks"" storage at room temperature. In the same fashion, if an emulsion comprising all-trans retinol had an initial concentration of 0.30% by weight and after storage for 13 weeks at 40xc2x0 C. had a concentration of all trans-retinol of 0.24% by weight, then the original emulsion retinol of 80% after 13 weeks"" storage at 40xc2x0 C.
Specifically, a commercially usable composition should exhibit a stability of at least about 60% of the active retinoid(s) after 13 weeks storage at 40xc2x0 C. Preferably, the compositions of this invention exhibit a stability of at least about 70% after 13 weeks"" storage at 40xc2x0 C.
Accordingly, there is provided, in accordance with the teachings of this invention, a skin care composition comprising an oil-in-water emulsion and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said composition having a pH of between about 4 and about 10; said composition further comprising an oil phase, said oil phase having a relatively low level of unsaturation; said composition further comprising a stabilizing system selected from the group consisting of:
a) at least one oil-soluble antioxidant;
b) a chelating agent and at least one oil-soluble antioxidant;
c) a chelating agent; and
d) a chelating agent and an antioxidant present in each of the oil and water phases of said emulsion; said composition retaining at least about 70% of said retinoids after 13 weeks"" storage at 40xc2x0 C.
Additionally, there are provided herein oil-in-water emulsions having novel emulsification systems. The oil-in-water emulsion compositions of this invention preferably contain:
a) an emulsifier system selected from the group consisting of:
i) a mixture of glyceryl stearate and polyethylene glycol 100 stearate;
ii) cetearyl alcohol and cetearyl glucoside;
iii) a mixture of a polyethylene glycol ether of stearyl alcohol of the formula:
CH3(CH2)16CH2(OCH2CH2)nOH 
wherein n is 21 and a polyethylene glycol ether of stearyl alcohol of the formula:
CH3(CH2)16CH2(OCH2CH2)nOH 
wherein n is 2; and
iv) a mixture of sorbitan stearate and polysorbate 60 (a mixture of stearate esters of sorbitol and sorbitol anhydrides condensed with 20 moles of ethylene oxide);
b) a co-emulsifier selected from the group consisting of: cetyl alcohol, stearyl alcohol and mixtures thereof;
c) an oil phase present in the amount of from about 2 to about 20 percent by weight of the total emulsion composition comprising:
i) a light, dry absorbable oil and
ii) substantive, emollient oils or waxes
wherein such dry absorbable oil and such substantive emollient oil are present in a ratio of from about 1:3 to about 10:1.
As described above, the composition of the invention is in the form of a particular type of emulsion, namely oil-in-water. As used herein, the generally accepted concept of an emulsion applies, i.e., an intimate mixture of two immiscible liquids which remains unseparated for an acceptable shelf life at or about room temperature. Ordinarily, when two immiscible liquids are mechanically agitated, both phases initially tend to form droplets. Thereafter, when the agitation ceases, the droplets quickly coalesce, and the two liquids tend to separate. On the other hand, an emulsion may be formed and physically stabilized and the lifetime of the droplets in intimate mixture materially increased if a compound, referred to as an emulsifier, is added to the immiscible liquids. Usually only one phase persists in droplet form for a prolonged period of time, and this is referred to as the internal phase which is surrounded by an external phase. An oil-in-water emulsion is one in which the external phase (also called the continuous phase) comprises water or an aqueous solution and the internal phase (also called the discontinuous or disperse phase) comprises an oil or mixture of mutually soluble oils.
A suitable vehicle for delivery of skin care active ingredients should combine a variety of features. It should be esthetically acceptable for its intended use, i.e. it should be compatible with other products including color cosmetics, it should be low or lacking in odor, easy to apply and spread, quickly absorbed and should leave a non-greasy but perceptibly functional residue. It should also be easily and quickly produced, cost-effective and have suitable physical stability under a variety of adverse conditions, such as high and low temperatures. It should also have a relatively long shelf life under normal commercial and residential environmental conditions.
The novel compositions of this invention should contain an esthetically acceptable oil phase composed of non-volatile compounds which remain on the skin after application. They should also contain an acceptable emulsification system which assists in maintaining the physical stability of the formulation. Surprisingly, the emulsification systems of this invention have been found to act to xe2x80x9cbalancexe2x80x9d the esthetic appearance and feel of the compositions while maintaining the physical stability of the compositions.
The emulsifiers useful in the compositions of this invention may be chosen from the following: (i) a mixture of glyceryl stearate and polyethylene glycol 100 stearate (available commercially as Arlacel 165 from ICI Americas); (ii) cetearyl alcohol and cetearyl glucoside (preferably in combination with cetearyl alcohol), available commercially as Montanov 68 from SEPPIC; (iii) a mixture of a polyethylene glycol ether of stearyl alcohol of the formula:
CH3(CH2)16CH2(OCH2CH2)nOH 
wherein n is 21 and a polyethylene glycol ether of stearyl alcohol of the formula:
CH3(CH2)16CH2(OCH2CH2)nOH 
wherein n is 2 (available commercially as Brij 721 and Brij 72 from ICI Americas); and (iv) a mixture of sorbitan stearate and polysorbate 60 (a mixture of stearate esters of sorbitol and sorbitol anhydrides condensed with 20 moles of ethylene oxide), available commercially as, respectively, Span 60 and Tween 60 from ICI Americas.
Two particularly preferred emulsification systems include (a) a mixture of glyceryl stearate and polyethylene glycol 100 stearate and (b) cetearyl alcohol and cetearyl glucoside. These emulsification systems permit the water and oil phases to be combined such that the oil phase forms droplets in the water phase. When incorporating system (a) into a composition of this invention, the ratio of glyceryl stearate to polyethylene glycol 100 stearate should be from about 1:1. When incorporating system (b) into a composition of this invention, the ratio of cetearyl alcohol to cetearyl glucoside should be from about 6:1 to about 3:1. The amount of emulsifier present in the compositions of this invention should be from about 1 to about 10 weight percent. More preferably, from about 1 to about 6 weight percent should be used. Most preferably, from about 1 to about 5 weight percent should be used.
In order to maintain the droplets as separate entities, and to prevent the phases from separating, accessory emulsifiers or xe2x80x9cco-emulsifiersxe2x80x9d are often utilized. These co-emulsifiers prevent the oil phase from coalescing or creaming and keep the phases physically stable as an emulsion prior to application to the skin. They lend xe2x80x9cbodyxe2x80x9d to the emulsion and give the formulation its character as a lotion or a cream by imparting viscosity to the composition. It has been found that particularly useful co-emulsifiers are fatty alcohols such as cetyl and stearyl alcohols and the like. Preferably, a mixture of cetyl and stearyl alcohols should be used as the co-emulsifier in most cases. Preferably, the ratio of cetyl alcohol to stearyl alcohol should be from about 2:1 to about 1:2. Preferably, the co-emulsifier should compose from about 1 to about 5 weight percent of the composition. The preferred ratio of emulsifier to co-emulsifier is from about 3:1 to about 1:10. More preferably, the ratio should be from about 3:1 to about 1:3.
The present invention also provides oil-in-water emulsion compositions containing at least one retinoid compound wherein the physical stability of the emulsion and the chemical stability of the active ingredients are excellent. The present invention also provides a method for making such emulsion compositions and a method and apparatus for storing such emulsion compositions in order to maintain their stability during storage and prior to use by the consumer. It should be noted, however, that the base emulsion, including the emulsifiers, co-emulsifiers and oil phase, of this invention may be used not only in combination with retinoids, but with a variety of active topical ingredients with or without the inclusion of retinoid materials.
The skin care compositions of the present invention comprising an oil-in-water emulsion can be in the format of cream or lotion formulations, as desired, by varying the relative quantities of the oil and water phases of the emulsion. The pH of the compositions should be in the range of from about 4 to about 10; preferably they should be from about 6 to about 8. It has been found that, in compositions having a pH of about 6 or more, the retinoid is more stable than at pH of less than 6. Furthermore, the stability of the retinol is less dependent upon the actual materials used in the formulation at pH of 6 or more.
Preferably, the oils used in the compositions of this invention are relatively highly saturated, preferably those having a relatively low iodine value. The contribution to unsaturation, density C, of an individual oil in the composition is calculated as follows:
C=Axc3x97B, 
where A is the percentage of the unsaturated oil or fat used in an oil-in-water emulsion and B is the iodine value of the unsaturated oil. If a mixture of oils is used in the oil phase, the total unsaturation density will be the sum of all individual C values. Accordingly, an oil phase having an unsaturation density or total C of 1200 or less and preferably 500 or less should be used in the formulations of this invention. It is theorized that saturated oils and/or fats are less reactive than unsaturated oils and fats, due to the presence of reactive double bonds in unsaturated oils and fats, which can initiate reactions with the retinoids and other materials in the compositions of this invention. Synthetic oils that are useful are fatty acid esters, fatty alcohols, for example, octyl hydroxystearate, cetyl palmitate, cetyl alcohol, glyceryl stearate and PEG-100 stearate, stearyl alcohol, octyl pelargonate and the like. Examples of preferred oils are as follows: Finsolv TN (available from Finetex of New Jersey), Miglyol 812 (available from Huls Corporation of New York), silicone oil (Dow Corning of Michigan), mineral oil, and the like, having very low iodine values are also quite useful in the compositions of this invention. Furthermore, the percentage of the oil present in the compositions of this invention is also relevant: the lower the percentage of high-iodine value oil, the more stable the retinoid in the composition.
When the emulsion compositions of this invention are applied to the skin, the aqueous portions of the compositions volatilize, while the non-volatile portion of the compositions of this invention remain upon the skin. The oil phase components along with the co-emulsifiers and emulsifiers make up this non-volatile portion of the compositions. Thus, the esthetics of the non-volatile portion are quite important in making the compositions of this invention.
It is desirable to compose an oil phase containing both at least one xe2x80x9cdryxe2x80x9d absorbable emollient oil and at least one substantive oil or wax. A dry absorbable emollient oil is needed for the purpose of quickly absorbing the composition into the skin. This dry absorbable emollient oil is generally not greasy, a desirable attribute. However, this attribute can be unpleasant if the dry absorbable oil is the only oil in the oil phase. Because such an oil is easily absorbed, it leaves no positive xe2x80x9cfeelxe2x80x9d on the skin. Therefore, it should be balanced with one or more substantive skin conditioning oils or waxes, which are soothing and coat the skin, leaving an xe2x80x9cafterfeelxe2x80x9d perceptible to the user. These substantive oils and waxes have these desirable traits, but, when used in excess, can leave a greasy feeling on the skin. Thus, the benefit of the emulsion base of this invention is that it balances the esthetics of the compositions with respect to the oil phase and has the capability of rebalancing it with respect to other ingredients which may provide active skin conditioning and/or therapeutic benefits. Preferably, the ratio of dry absorbable emollient oil to substantive skin conditioning oils is from about 1:3 to about 10:1. More preferably, the ratio is from about 1:3 to about 5:1. Most preferably, the ratio should be about 1:1. The dry absorbable emollient is most preferably C12-15 alkyl benzoate (commercially available as Finsolv TN from Finetex), capric-caprylic triglycerides (commercially available from Huls as Miglyol 812) or other suitable synthetic triglycerides known to those of skill in the art. Substantive oils or waxes may be selected from white petrolatum, octyl hydroxystearate, cetyl palmitate and the like. The total amount of oil phase may vary from a very low level, e.g., about 2% of the overall composition, to as much as about 20% of the composition. More preferably, the oil phase should be composed of from about 5 to about 12% of the composition in order to provide the desired spreadability and consistency without leaving excessive residue with the perception of greasiness and oily coating on the skin. Variations within this range may depend upon the characteristics of the additional components, including vitamins, sunscreens and the like, both to serve as a vehicle to apply the active ingredients properly to the skin and to modify the sometimes undesirable esthetics contributions from these components.
In addition to such oils, other emollients and surface active agents have been incorporated in the emulsions, including glycerol trioleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1) monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol (50) monostearate, octylphenoxypoly (ethyleneoxy) ethanol, decaglycerin penta-isostearate, sorbitan sesquioleate, hydroxylated lanolin, lanolin, triglyceryl diisostearate, polyoxyethylene (2) oleyl ether, calcium stearoyl-2-lactylate, methyl glucoside sesquistearate, sorbitan monopalmitate, methoxy polyethylene glycol-22/dodecyl glycol copolymer (Elfacos E200), polyethylene glycol-45/dodecyl glycol copolymer (Elfacos ST9), polyethylene glycol 400 distearate, and lanolin derived sterol extracts, glycol stearate and glycerol stearate; alcohols, such as cetyl alcohol and lanolin alcohol; myristates, such as isopropyl myristate; cetyl palmitate; cholesterol; stearic acid; propylene glycol; glycerine, sorbitol and the like.
It is also preferable to have at least one oil-soluble antioxidant in the compositions of this invention. The oil-soluble antioxidants which are useful in the compositions of the present invention include butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), phenyl-a-naphthylamine, hydroquinone, propyl gallate, nordihydroguaiaretic acid, rosemary extract and mixtures thereof as well as any other known oil-soluble antioxidant compatible with the other components of the compositions.
Preferably, a water-soluble antioxidant should be present in the water phase of the compositions of this invention. The water-soluble antioxidants which are useful in the compositions of this invention include ascorbic acid, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid, thioglyerol, thiosorbitol, thiourea, thioglycolic acid, cysteine hydrochloride, 1,4-diazobicyclo-(2,2,2)-octane, malic acid, fumaric acid, licopene and mixtures thereof as well as any other known water-soluble antioxidant compatible with the other components of the compositions.
The composition of this invention can contain additives, as required, such as a humectant, an antioxidant, a preservative, a flavor, fragrances, a surface active agent, a binder, and the like, as well as skin protectant agents, therapeutic agents and xe2x80x9ccosmeceuticalsxe2x80x9d.
Preferably, a detackifying material should be incorporated into the compositions of this invention. When emulsions are applied to the skin, they break apart. Often, they leave a sticky feeling as they dry before the emulsion has totally broken and been absorbed into the skin. This is particularly true of emulsions containing cetyl and stearyl alcohols, due to the liquid crystal nature of these materials, as they are quite slow to give up water upon application to the skin. Unexpectedly, it has been found that certain detackifying materials may be added to the compositions of this invention in order to combat this stickiness. Materials having a xe2x80x9ctalc-likexe2x80x9d character, i.e., which crystallize into a plate-like form, are preferable for use as they add lubricity to the compositions of this invention. Other non-platey solids, although less preferably, are also acceptable for use as a detackifier. Preferably, the detackifying material used in the compositions of this invention should be lauroyl lysine, titanium dioxide, zinc oxide, pulverized nylon, oatmeal and surface treated oatmeal, silica, mica, barium sulfate, aluminum starch, octenyl succinate, micronized polyethylene, boron nitride, corn starch, talc or silicone waxes or oils and other insoluble particles which do not leave visual residue on the skin. More preferably, the detackifying material should be lauroyl lysine, boron nitride, mica and talc. Most preferably, the detackifier should be lauroyl lysine (such as Amihope LL commercially available from Ajinomoto). Preferably, the detackifier is present at very low concentrations, i.e., from about 0.01 to about 7% by weight. More preferably, it should be present at the amount of from about 0.5 to about 1% by weight. Other detackifying materials which are compatible with fatty emulsions would also be appropriate for use in the compositions of this invention.
Surprisingly, it has also been found that small concentrations of lower alkyl alcohols also contribute an esthetically benefit to the compositions of this invention. It has been found that the addition of lower alkyl solvent alcohols mitigate the waxy feel of the emulsions on the skin due to the presence of cetyl and stearyl alcohols. It is believed that lower alkyl alcohols assist in solubilizing the liquid crystal structures formed by these fatty alcohols. Preferably, lower alkyl alcohols having from one to four carbon atoms are useful in the compositions of this invention. Most preferably, ethyl alcohol should be present in the compositions of this invention. Preferably, they should be present in an amount of from about 2 to about 10% by weight of the compositions.
Examples of the humectant include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol and the like. They may be used either singly or in combination.
Examples of the preservatives include salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate and the like.
Examples of the flavor and fragrance include menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like.
Examples of surface active agents include sodium alkyl sulfates, e.g., sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodium dioctylsulfosuccinate; N-alkylaminoglycerols, e.g., N-lauryldiaminoethylglycerol and N-myristyldiaminoethylglycerol, N-alkyl-N-carboxymethylammonium betaine and sodium 2-alkyl-1-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerol ester, sorbitan aliphatic acid ester, Pluronic type surface active agent, and polyoxyethylenesorbitan aliphatic acid esters such as polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan monolaurate. Emulsifier-type surfactants known to those of skill in the art should be used in the compositions of this invention.
Examples of the binder or thickener include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as preservatives such as methylparaben, butyl paraben, propylparaben and phenoxyethanol, coloring agents and fragrances also are commonly included in such compositions.
The antioxidants should be utilized in a stabilizing effective amount and may range in total from about 0.001 to 5% based on the weight of the total composition, preferably from about 0.01 to about 1%. The amount of antioxidants utilized in the compositions of the present invention is dependent in part on the specific antioxidants selected, the amount of and specific retinoid being protected and the processing conditions.
In certain aspects of this invention, the compositions should include a chelating agent. The retinoid compounds of this invention are sensitive to metal ions and in particular to bi- and tri-valent cations and in certain instances, appear to degrade rapidly in their presence. The chelating agent forms a complex with the metal ions thereby inactivating them and preventing them from affecting the retinoid compounds. Chelating agents which are useful in the compositions of the present invention include ethylenediamine tetra acetic acid (EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, citric acid, tartaric acid, and mixtures thereof. The chelating agents should be utilized in a stabilizing effective amount and may range from about 0.01 to about 2% based on the weight of the total composition, preferably from about 0.05 to about 1%. Most preferably, the chelating agent should be EDTA.
The retinoid compounds which are useful in the compositions of the present invention consist of Vitamin A alcohol (retinol), Vitamin A aldehyde (retinal) and Vitamin A esters (retinyl acetate and retinyl palmitate), although other retinoids may be incorporated into the emulsion compositions of this invention. These retinoids are utilized in the compositions of the present invention in a therapeutically effective amount that may range from about 0.001 to about 5% by weight of the total compositions, preferably from about 0.001 to about 1%.
Other active ingredients such as sunscreen materials and antimicrobial materials may be utilized in the compositions of the present invention provided that they are physically and chemically compatible with the other components of the compositions. For example, moisturizing agents such as propylene glycol, allantoin, acetamine MEA, oat protein and hyaluronic acid and other humectants may be added to the retinoid-containing formulations of this invention in order to provide moisturizing activity in conjunction with the retinoid-related activity of the products. Other proteins and amino acids may also be incorporated. Sunscreens may include organic or inorganic sunscreens, such as octylmethoxycinnamate and other cinnamate compounds, titanium dioxide and zinc oxide and the like.
Various irritancy mitigants may be added to the compositions of this invention. Retinoid-containing compositions tend to irritate the skin, therefore irritancy mitigants assist in preventing undue discomfort to the user, while potentially permitting the dosage level of retinoid to be increased, thereby making the product more effective. Irritancy mitigants such as a-bisabolol, panthenol, green tea extract, allantoin, ginkgo biloba, stearoyl glycyrrhetinic acid (licorice extract), tea tree oil, butchers"" broom, calendula, ginseng and the like may be added.
It has also been found, surprisingly, that certain materials provide a mitigation of irritation due to retinoids which have not previously evidenced or would have been expected to evidence such activity. For example, retinoid-containing compositions which also contain octylmethoxycinnamate had very low irritation on the skin when compared with identical compositions which did not contain octylmethoxycinnamate. Generally, it has been found that certain compounds afford lower irritation in formulations containing similar levels of retinoid than formulations which do not contain such irritation-mitigation agents.
It has been observed that compounds having similar solubility attributes to those of retinoid compounds tend to mitigate irritation caused by such compounds (hereinafter, xe2x80x9cirritation mitigation agentsxe2x80x9d). Solubility attributes of two or more materials with respect to each other are generally reflected in the xe2x80x9csolubility parameterxe2x80x9d, xcex4, which is expressed in the units (cal/cm3)xc2xd. It is believed that the presence of the irritation mitigation agents having similar solubility properties to those of retinoid compounds tend to assist in solubilizing the retinoids in the oil phase. Due to the fact that retinoids tend to be oil-soluble, the irritation mitigation agents of this invention should also preferably be oil-soluble such that the irritation mitigation agents and retinoids are present in the same, oil phase. The irritation mitigation agents, it is believed, thereby act within the oil phase to maintain the retinoids in that phase and delay and/or modulate their release to the skin upon topical application. The retinoids therefore tend to be delivered to the skin in a more even dose rather than as a xe2x80x9cbolusxe2x80x9d in a high dose. This modulation in delivery to the skin is the most likely cause of the decreased irritation.
It is believed that irritation mitigation agents having a solubility parameter xcex4 close to that of the retinoid compounds utilized in the compositions of this invention will modulate delivery to the skin and consequently decrease irritation engendered by the retinoids. The value of the solubility parameter can be estimated from tabulated molecular substituent constants such as those described by Fedors. These substituent constants can be found in Solubility and Related Properties by Kenneth C. James, pp. 185-187, Marcel Dekker, Inc. (1986). Generally, according to Textbook of Polymer Science, 2nd Ed., Billmeyer, solubility can be expected if the difference of the solubility parameters of two materials is less than about 2 units. More preferably, the difference of the solubility parameters should be less than 1.5 units and, more preferably, less than 1 unit.
One or more irritation mitigation agents may be useful in effecting irritation mitigation in a given composition according to this invention. In effect, the oil phase can be regarded as providing irritation migitating effects dependent upon the solubility attributes of the phase and/or its components. Furthermore, a combination of materials which alone might not be effective may be useful in mitigating irritation, depending upon the solubility parameter of the combination. The solubility of a blend of materials may be found according to the following formula:
xcex4blend=xcexa31xe2x88x92n{(xcex41xc3x97V1)+(xcex42xc3x97V2)+. . . +(xcex4n+Vn)}
where V represents the volume fraction of the particular material in the composition (See Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Ed.).
Preferably, the irritation mitigation agents of this invention are oil-soluble compounds, more preferably, organic ester compounds. More preferably, oil-soluble organic ester compounds having a solubility parameter within 2 units of that of a retinoid compound should be useful in mitigating retinoid irritation. For example, the irritation mitigation agents may be selected from esters of fatty acids and/or esters of fatty alcohols. Most preferably, the oil-soluble organic ester compounds are selected from the following group: C12-15 Alkyl benzoate, octyl methoxycinnamate, octocrylene, menthyl anthranilate, homomenthyl salicylate, glyceryl stearate, PEG 100 stearate, and stearyl lactate or a mixture thereof. Effective compounds may also be selected from the following: octyl dimethyl PABA, cetyl alcohol, stearyl alcohol, and the like, i.e., organic compounds having a carbon chain having from about 12 to about 18 carbon atoms and an appropriate solubility parameter.
Preferably, the irritation mitigation agent (such as octyl methoxycinnamate) should be present in an amount from about 3 to about 12 weight percent of the formulation. More preferably, the irritation mitigation agent should be present in an amount from about 3 to about 6 weight percent of the composition.
It is believed that such organic esters may control retinoid delivery in that they may solubilize or associate with the retinoid. Alternatively, hydrolysis of these esters may produce aromatic carboxylic acids, which may act as weak anti-inflammatory agents.
Other ingredients may include agents which assist in protecting the skin from aging, such as sunscreens, anti-oxidant vitamins such as ascorbic acid, vitamin B, biotin, pantothenic acid, vitamin D, vitamin E and vitamin C. Yeast extract, gingko biloba, bisabolol, panthenol, alpha hydroxy acids and oligosaccharides such as melibiose are among other ingredients which assist in preventing aging of the skin by such means as irritation mitigation, oxidation mitigation, healing, affecting retinoid metabolism and inhibiting the production of elastase.
Skin color evening ingredients and depigmentation agents may also be effective in the products of this invention. Such ingredients may include hydroquinone, licorice extract, kojic acid, gatuline A (pilewort extract), micromerol (butylene glycol and apple extract), glutathione, arbutin, placenta extract, ascorbic acid, magnesium-L-ascorbyl-2-phosphate and the like.
Compositions which assist in the reduction of lines and wrinkles may also be added to the compositions of this invention. For example, alpha hydroxy acids, hyaluronic acid, Gatuline R (fagus silvitica extract), pigments and scattering aids such as mica, zinc oxide and titanium dioxide may be used in the compositions of this invention in this capacity. Various natural extracts such as tannins, fiavenoids, saponins and the like may also be added.
Anti-inflammatory agents may also be used in the compositions of this invention. Not only should these agents assist in mitigating irritation, they may assist the retinoids in treating wrinkles and lines in the skin. Steroidal anti-inflammatory agents, including but not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxycorticosterone acetate, dexamethasone, dichlorisone, deflorasonediacetate, diflucortolone valerate, fluadronolone, fluclarolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocionide, flucortine butylester, fluocortolone, flupredidene (flupredylidene) acetate, flurandronolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenalone acetonide, medrysone, amciafel, amcinafide, betamethasone and its esters, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and mixtures thereof may be used. Preferably, hydrocortisone may be used.
Nonsteroidal anti-inflammatory agents may also be employed in the compositions of this invention, such as salicylates (including alkyl and aryl esters of salicylic acid), acetic acid derivatives (including arylacetic acid and its derivatives), fenamates, propionic acid derivatives and pyrazoles or mixtures thereof. Other synthetic and natural anti-inflammatory agents may also be used.
Additional active ingredients having topical activity may be utilized in the compositions of this invention. Azole-type anti-fungal and anti-bacterial agents may be employed in the compositions of this invention in their base form. For example, ketoconazole, miconazole, itraconazole, metronidazole, elubiol, and like related imidazole antifungals and antibacterials are useful in the topical formulations of this invention.
The compositions of the present invention can be prepared by well-known mixing or blending procedures. Each phase of the emulsion is preferably separately prepared with all of the components contained in the appropriate phase, except that it is usually preferred to omit the retinoid compound initially. The emulsion is then formed normally by adding the oil phase to the water phase with agitation. Preferably, the water phase should be added into the oil phase, as it results in increased stability. It is preferred that the portions be prepared under oxygen-depleted atmosphere such as a nitrogen or argon gas blanket. Most preferably, argon or nitrogen gas is bubbled through the water phase prior to phasing in the oil phase. Commercially, it is envisioned that such oxygen depleted atmosphere may be obtained by operating under vacuum conditions and that the product be stored, prior to use, in blind-end containers, preferably aluminum tubes.
This invention relates not only to stable and esthetic retinoid-containing compositions used in skin care, and to methods of making such compositions, it also relates to an apparatus and method of storing such compositions prior to use. Previously, numerous products containing retinol or its esters or aldehyde have been marketed in packages which follow the convention for personal care products in being composed of principally low or high density polyethylene or polypropylene usually containing a pigmenting substance included within the package resin. Although this package technology is ordinarily suitable for toiletries, it has been found that these package materials are not satisfactory for retinoid materials, particularly retinol and retinal, as they transmit sufficient light combined with sufficient oxygen to lead to degradation of the vitamin substance into foreign materials not ordinarily found in mammalian metabolism, such as a variety of cis-isomers of the polyene moiety of the retinoid side chain, as well as oxidative degradation products and hydrolysis products. It has been found that a combination of proper manufacturing procedures as described can provide the fresh product in suitable form to the consumer, but over time, without exclusion of the destabilizing influences of light and oxygen, the foreign degradative substances accumulate, reducing the extent of the desirable attributes of the product.
In some cases, such as the retinaldehyde-containing product xe2x80x9cYsthealxe2x80x9d, commercially available from Pierre Fabre of France, a package structure which minimizes the tendency of the package to inhale air after dispensing product has been used, thus minimizing the exposure of product to oxygen. However, since the package is made of pigmented polypropylene, it is not sufficiently protective of light intrusion into the product. Many package forms, such as plastic tubes, bottles, or jars, are ineffective in protecting product from either air or light.
The skin care composition should neither be directly contacted with oxygen or an oxygen-containing gas such as air, nor contacted with oxygen passing through the wall of the container. Portions in contact with the outside, which constitute the container, such as a wall, an opening, etc. of the container, are required to have excellent oxygen barrier properties. The container must also be designed not to pass oxygen when feeding the skin care composition to the container or when removing the composition from the container.
If has been found that sufficient exclusion of these destructive influences may be obtained only by use of packages constructed in part of aluminum, which is totally opaque to light and totally excludes oxygen permeation of the package walls. Additionally, given that the aluminum is not elastic, unlike plastic tubing, it has minimal tendency to suck back air after dispensing product. Another package structure which is adequate to protect retinoid-containing products is that constructed with plastic film laminates including a layer of aluminum foil. The aluminum foil provides the protection of the aluminum tube, while the plastic film layers permit more conventional package esthetics. Another construction which is highly desirable for retinoid product protection is one which is constructed of aluminum foil or aluminum plastic laminate films of thin gauge and of broad and thin dimensions, sufficient so that the package can collapse as product is withdrawn, preventing air inhalation after product is dispensed. Such foil structures may be contained within a physically protective and esthetic oversleeve of conventional plastic, enabling safe shipping and handling during processing, as well as when it reaches consumers.
It has also been found that by using a pouch-type container in which a composition is out of contact with oxygen, the composition can be used as not only a water-in-oil type emulsion but also an oil-in-water type emulsion. Further, even after use is begun, the contact with oxygen can be blocked, making it possible to substantially prevent decomposition or degradation of the retinoid in the skin care composition.
More specifically, this invention relates to a container in which the skin care composition is out of contact with oxygen in a two-compartment container such as a pouch-type container, further to a skin care composition which is stored in a two-compartment container which are made of films. Preferably, the film materials of the inner container are formed from a monolayer film or multilayer film. The film materials are preferably selected from the following materials: aluminum and AAS and ethylene-vinyl alcohol copolymer. More preferably, the pouch-type container contains film materials which are laminated in the following order, beginning from the innermost portion of the film: polyethylene terephthalate, nylon, aluminum and an AAS resin or polypropylene. Further, this invention relates to a skin care composition which is stored in a container having an aerosol-system using a liquefied gas or a compressed gas.
If such a requirement is satisfied, the shape of the container in which the composition is out of contact with oxygen is not particularly limited in this invention, and can be a tube, a pump dispenser, a compressed dispenser, a bottle, a spray, a sachet or the like. From the aspects of production, treatment and an oxygen-barrier type, the two-compartment container is preferred and, the pouch-type container is especially preferred. Such a two-compartment container generally means a container consisting of an outer container and an inner container which is accommodated in the outer container and stores the content therein, but is not particularly restricted if the container can store and isolate the content from outside. A xe2x80x9cpouch-type containerxe2x80x9d means a container having an outer container and a pouch which is accommodated in the outer container, is provided with a valve which stores the contents therein.
This pouch is a bag-like container whose wall is formed of a film and which is provided with an opening through which to pass the contents. The two-part container actually used is preferably an aerosol-system. The aerosol-system here referred to is a system in which the inside of the container is kept in a state pressurized with a propellant, and the content is sprayed with the propellant by opening a valve, or a system in which the content is discharged outside the container with the pressure of the propellant.
A liquefied gas or a compressed gas is used as a propellant. Examples of the liquefied gas include chlorofluorocarbons, dimethyl ether, liquefied petroleum gas (LPG) and chlorinated hydrocarbons. Examples of the compressed gas include a nitrogen gas, a carbon dioxide gas, a nitrous oxide (N2O) and argon. The liquefied gasses are preferable when considering a uniformity of discharge amount of the content, and the compressed gasses are preferable in minimizing interaction with the content, influence on the human body and the like.
An ordinary aerosol is generally formed by charging a stock solution and propellant in a container and sealing the container with a valve. In a general filling method, the content is charged into the container from an opening, and after the opening is sealed with a valve the propellant is further charged. According to such an ordinary filling method, however, it is quite difficult to prevent the contact between the content such as a lotion or the like and oxygen. There is further a problem that the content is directly contacted with the propellant within the pouch by being partially mixed therewith. Taking into account the problem of stability of the retinoid compound, the container of the ordinary aerosol-system in which the content is mixed with the propellant cannot be used in the skin care composition of this invention.
Accordingly, the two-part container in this invention, unlike the ordinary container, consists of an outer container and a pouch having a valve. Only the content (skin care composition) is contained in the inner container and the propellant is not; along with the inner container, the propellant is stored in the outer container. Similarly the pouch-type container of this invention consists of an outer container and a pouch having a valve. Only the skin care composition is contained in the pouch and the propellant is not; along with the pouch, the propellant is stored in the outer container. Employment of such a method prevents the contact between the skin care composition and the propellant, thereby making it possible to prevent decomposition or degradation of the retinoid in the skin care composition.
A method of filling the contents in the inner container is not particularly limited and methods such that the oxygen does not invade the inner container and not contact the contents may be applicable, as known to those of ordinary skill in the art. Preferably, the contact between oxygen and the skin care composition of this invention should be performed such that filling takes place in an atmosphere of inert gas such as nitrogen or argon. The content is filled in the pouch as follows. First, the pouch and propellant are placed within the outer container and said outer container is then sealed with the valve. In this state, a gas within the pouch is expelled with the pressure of the propellant so that the inside of the pouch is almost completely degassed. After that, the content is filled in the pouch under pressure. The content is, when filled by this method, scarcely contacted with oxygen in the filling. Preferably, if the content is filled in inert gas such as nitrogen or argon, the contact with oxygen is more completely blocked.
Further, even after the content is filled, it is double partitioned from the open air by an oxygen-impermeable film used in the pouch and the outer container, and the contact between oxygen in an ambient atmosphere and the skin care composition within the pouch is completely prevented.
The conventional tube-type container is completely sealed before first opened. However, once it is opened and started to be used, entrance of oxygen is permitted whenever it is opened for use, though the contact with air is prevented with a cap during storage. Meanwhile, when the two-part container is used, oxygen does not enter even after starting to use it.
The material of the container of this invention in which the composition is out of contact with oxygen is not particularly limited. However, a multilayered film constituting the inner container in the two-compartment container is preferable, from the aspects of sealing retention, oxygen-barrier properties and stability to the skin care composition. More preferable is a multilayered film composed of at least two kinds selected from the group consisting of polyethylene terephthalate, nylon, aluminum, polypropylene, an AAS resin and an ethylene/vinyl alcohol copolymer. Especially preferable are a multilayered film obtained by laminating polyethylene terephthalate, nylon, aluminum and the AAS resin in this order as film materials from the innermost layer to the outermost layer of the pouch, and a multilayered film obtained by laminating polyethylene terephthalate, nylon, aluminum and polypropylene in this order as materials from the innermost layer to the outermost layer.
Polyethylene terephthalate is a polyester resin having a chemical structure obtained by polycondensing terephthalic acid with ethylene glycol. Nylon includes various polyamide resins. The AAS resin is a resinous polymer formed by graft polymerizing acrylonitrile as a main component with copolymer components including an acrylate ester and butadiene, and can be obtained, for example, under a trade name xe2x80x9cBAREXxe2x80x9d from Mitsui Toatsu Chemicals, Inc.
The ethylene/vinyl alcohol copolymer is a resinous polymer produced by saponifying a random copolymer of ethylene and vinyl acetate, and be obtained, for example, under a trade name xe2x80x9cEVALxe2x80x9d from Kuraray Co., Ltd.
The two-part container of this invention can be used, as is apparent from the foregoing explanation, in not only the retinoid-containing skin care composition but also liquid substances of various forms, e.g., an emulsion, a suspension, an aqueous solution and an oil. Especially, it is suitable for storage of substances required to protect the content from an external environment such as air.